This application is for a bi-institutional collaborative Exploratory/Developmental Award in Epilepsy Research for Junior Investigators. The PI is an Assistant Professor at the University of Kentucky, and although published extensively in the field of mitochondrial bioenergetics and mitochondria-mediated cellular injury and death, he is relatively new to the field of epilepsy research. During a post-doctoral fellowship, the PI initiated an innovative collaboration with an established epilepsy researcher at the University of California at Irvine. The co-PI is an expert on mechanisms underlying the anticonvulsant actions of the ketogenic diet (KD), an effective non-pharmacological treatment for medically refractory epilepsy. The KD is a high-fat, low-carbohydrate/low-protein diet designed to reproduce the early biochemical changes seen upon fasting. Despite decades of successful clinical experience with the KD, the mechanisms underlying its anticonvulsant actions remain poorly understood. It is well known that fasting increases peripheral mitochondrial uncoupling protein (UCP) activity. However, there are no data addressing the effects of a KD on brain mitochondrial uncoupling. In preliminary studies, we have found that a KD enhances mitochondrial uncoupling and decreases reactive oxygen species (ROS) production in normal mouse cortex. The fundamental goal of the proposed studies is to determine whether a KD decreases mitochondrial oxidative damage in the hippocampus of developing epileptic mice (i.e., the Kcnal-null mutant), and following acute excitotoxic insult in normal mice. Specifically, we hypothesize that a KD increases UCP-mediated mitochondrial uncoupling and reduces subsequent ROS formation in epileptic hippocampus. Additionally, we hypothesize that the KD reduces mitochondrial dysfunction, lipid peroxidation and protein oxidation following kainic acid-induced seizures. Our preliminary data in the kainic acid model strongly suggest a direct neuroprotective effect of the KD, not related to seizure severity between groups of control diet- vs. KD-treated animals. The results of these studies will shed light on whether a KD reduces oxidative stress in a genetic model of developmental epilepsy, as well as in a well-established excitotoxic model. The clinical importance of such findings is that this therapy may ameliorate the epileptic condition itself, and not merely halt spontaneous recurrent seizure activity.